Beta-(cyclic amino)-alpha-hydroxy-alkanals



United States Patent BETA-(CYCLIC AMINO)-ALPHA-HYDROXY- ALKANALS John B. Wright and Edward H. Lincoln, Kalamazoo Township, Kalamazoo County, Mich., assignors to The Upjohn Company, Kalamazoo, Mich., a corporation of Michigan No Drawing. Filed Apr. 30, 1956, Ser. No. 581,272 6 Claims. (Cl. 260294.7)

The present invention relates to novel B-(cyclic amino} a-hydroxyalkanals of the formula B-formyl-B-hydroxy-(lower-alkyD-N R wherein is a cyclic amino radical containing from five to ten ring members, inclusive, which ring members are the said nitrogen atom N, carbon atoms, and not more than one additional hetero atom selected from the group consisting of nitrogen, oxygen and sulfur, and wherein loweralkyl contains from two to five carbon atoms, inclusive; acetals thereof wherein an acetal radical contains from three to nine carbon atoms, inclusive; and acid addition compounds thereof. Of particular interest are the B-(moncyclic amino)-u-hydroxypropionaldehydes of the formula wherein is a monocyclic amino radical coutaining'from five to seven ring members, inclusice, in a single ring, which ring members are carbon atoms and from one to two nitrogen atoms, inclusive; dialkyl acetals thereof wherein alkyl contains from one to four carbon atoms, inclusive; and mineral acid addition compounds thereof. Of most interest are the fi-(carbomonocyclic amino)-c-hydroxypropionaldehydes of the formula wherein .is a carbomonocyclic'amino radical containing in a single eggs after 216 hours (e.g. five Patented .Feh. 14, 1961 are useful for virus prophylaxis and decontamination of areas and materials and can readily be applied as the active ingredient in solutions, emulsions and suspensions for spraying, washing, painting, immersing, etc., dusts, aero sols, fumigants, etc., according to methods and procedures Well known in the pesticide and disinfectant arts. Usually the acid addition compounds of the present invention are employed for the foregoing purpose since they are more stable and have greater water solubility than the parent free base compounds of this invention, and, therefore, said acid addition compounds are a preferred embodiment of the invention for the foregoing use. The ,B-(cyclic amino)-a-hydroxy-alkanal acetals of the present invention are useful for the production of the alkanal free bases and acid addition compounds thereof of-the present in vention. Gther objects of the present invention, and uses of the novel compounds thereof, will be apparent to one skilled in the art.

Efficacy of the present antiviral compounds is illustrated by Table I Which shows the typically superior results of representative compounds obtained in the wellknown in ovo survival test for antiviral potency, employing Newcastles virus (NJ-KD strain) and influenza A virus (PR8 strain) as illustrative viruses. In the test method used to obtain the data in Table I any particular test compound, is dissolved in water or suspended in water-carboxymethyl cellulose, depending on the degree of water solubility. A known volume of such a solution or suspension containing a known concentration of the test compound is injected into the allantoic sac of tenday fertile eggs, using the technique described by Beveridge and Burnet, Medical Research Council, Special Report Series No. 256, The Cultivation of Viruses and Rickettsiae in the Chick Embryo, London, His Majestys Stationery Office, 1946. The test compound is usually administered at or slightly less than the maximum tolerated dose, i.e., the greatestamount which when similarly administered is found to cause no deaths in similar eggs during a 216-hour incubation period. The same volume of the same menstruum without test compound is injected into similar eggs as a control. About fifteen minutes later all eggs, test and control, are inoculated with a virus suspension containing approximately fifty times the ELD dosage of virus; one LD is that amount which kills fity percent of virus-infected embryonated eggs. The eggs are incubated at 37 degrees centigrade. Survivorship is determined by candling the eggs at eight-hour intervals during a 2l6-hour period. The protection afiorded by a test compound is conveniently expressed thus: percent survivorship of treated eggs after 216 hours (e.g. ninety percent) minus percent survivorship of control percent) equals the protective index (e.g. the maximum protective index Value being 100. The test compounds listed in Table I,

therefore, are highly potent antiviral agents.

TABLE I Test Compound Protective Index Milli- New- Influenza Formula grams per castles A Virus egg Virus CHf-O'Hz N-CH -CHOH-CHO-HCL 2.0 46

CHr-C a GET-CH2 I on. N-cm-CHQH-CHO-Hm 1:3 g9

GHQ-CH1 TI 4. 43 (BHr-CHOH-CHOCHCI The B-(cyclic amino)-a-hydroxyalkanals of the present invention are suitably prepared by reaction of an acid .addition compound thereof with a base, e.g. sodium hydroxide, sodium carbonate, calcium carbonate, etc., in an aqueous or aqueous organic solvent, followed by extraction of the free base with an organic solvent, drying of the solvent extract, and evaporation of the organic solvent. The acid addition compounds of the present invention are prepared by reaction of the parent free base or preferably a derivative thereof, e.g. an acetal thereof, preferably the diethylacetal, with an acid. Suitable acids are hydrochloric acid (especially preferred), hydrobromic acid and other hydrohalic acid, sulfuric acid, phosphoric acid, and other mineral acid, acetic acid, formic acid, benzoic acid, trichloroacetic acid, succinic acid, maleic acid, citric acid, tartaric acid, phenylacetic acid, oxalic acid, furoic acid, aand fl-cyclopentylpropionic acid, w and p-phenylpropionic acid, and other acids, particularly those having a pK, value below five, the K value being a common measure of acid strength (Moeller, Inorganic Chemistry, John. Wiley and Sons, Incorporated, New York, New York, 1952, pages 313-315). The B-(cyclic amino)-a-hydroxyalkanals or preferably a derivative thereof, e.g. an acetal, preferably the diethyl acetal, of the present invention are prepared by reaction of a cyclic secondary amine, the amino nitrogen being in the ring, with an a,p-epoxyalkana.l or preferably a derivative thereof, e.g. an acetal, preferably the diethyl acetal, which epoxy compound in turn is prepared from the corresponding a,fl-alkenal or derivative thereof, e.g. an acetal, preferably the diethyl acetal. These reactions can be illustrated, using the preferred diethyl acetal derivative, by the equation While the fl-(cyclic amino)--hydroxyalkanal diethyl acetal is the preferred acetal of the present invention, the dipropyl acetal, dibutyl acetal, dimethyl acetal, ethylene acetal, 1,2-propylene acetal, 1,3-propylene acetal, 1,2- butylene acetal, etc. also are included within the scope of the invention.

The following examples are illustrative only and are not to be construed as limiting the scope of the present invention.

Example 1 In a 100-milliliter flask fitted with a reflux condenser is placed a solution of 29.2 grams (0.20 mole) u,B-epoxypropionaldehyde diethylacetal, seventeen grams (0.20 mole) piperidine and three milliliters methanol. After a few minutes the solution boils quite vigorously and becomes yellow in color. After the boiling subsides the solution is heated on the steam-bath for two hours. The orange reaction mixture is distilled through a ten-inch, glass-helice-packed column. The product, B-piperidino-ahydroxypropionaldehyde diethylacetal cmwmnNcmomomomo0mm boiling point 143-145 degrees centigrade at 13.5 millimeters pressure, is collected as a pale yellow liquid in a yield of 41 grams (89 percent); 11 1.4550.

7 Analysis. -Calcd. for C H NO C, 62.30; H, 10.89; N, 6.06. Found: C, 62.20, 62.45; H, 10.99, 10.80; N, 6.06, 6.14.

In the same manner fl-piperidino-a-hydroxypropionaldehyde dimethyl acetal, dipropyl acetal, ethylene acetal, and dibutyl acetal are prepared from the corresponding depoxypropionaldehyde acetal.

, Example 2 A solution of seventeen grams (0.074 mole) fl-piperidino-a-hydroxypropionaldehyde diethylacetal and 150 milliliters of ten percent hydrochloric acid is prepared and warmed on the steam-bath for one hour. The pale yellow solution is concentrated on the steam-bath at reduced pressure. The pale yellow, solid material is dried with benzene and crystallized from 225 milliliters ethyl alcohol and 225 milliliters ethyl acetate. The white crystalline material is filtered and washed with ether. The product, p-piperidino-a-hydroxypropionaldehyde hydrochloride omwnomomcmomone-n01] melting point 155.5156.5 degrees centigrade, is collected in a yield of nine grams (64 percent). On recrystallization from 150 milliliters ethyl alcohol and milliliters ethyl acetate, the product, melting point 156-157 degrees centi)grade, is obtained in a yield of 7.5 grams (52.5 percent Analysis.--Calcd. for c,H ,c1No C, 49.61; H, 8.33; Cl, 18.31. Found: C, 49.80; H, 8.28; Cl, 18.37.

Substitution of hydrobromic acid or sulfuric acid for the hydrochloric acid in the foregoing procedure provides fl-piperidino a hydroxypropionaldehyde hydrobromide and sulfate, respectively.

Example 3 ,To a solution of p piperidinoa-hydroxy ropionaldehyde hydrochloride in water is added the theoretical which decomposes on standing for several days. Treatment of freshly prepared free base with the theoretical amount of acetic acid provides fl-piperidino-u-hydroxypropionaldehyde acetate [CH2(OH2)4NCH:CH(OH)CHO-CHaCOzH] In the same manner other acid addition compounds of p-piperidino-a-hydroxypropionaldehyde are prepared including the benzoate, furoate, propionate, phenylacetate, and p-cyclopentylpropionate.

Example 4 A mixture of 35.49 grams (0.3008 mole) of benzirnidazole, 43.8 grams (0.300 mole) of a,;8-epoxypropionaldehyde diethylacetal and 100 milliliters of ethanol is heated on a steam-bath with stirring for three and one-half hours and then allowed to stand overnight. The mixture is then concentrated in vacuo to a thick reddish-brown liquid. To the residue is added fifty milliliters of acetone and then Skellysolve B (mixture of hexanes) is added at the boiling point until the solution becomes turbid. The solution is placed in the refrigerator and the solid that precipitates is removed by filtration; weight 60.2 grams; melting point 76-85 degrees centigrate. The crude material is purified by boiling it with 500 milliliters of anhydrous ether. There is obtained 41.7 grams (53 percent) of a white crystalline solid melting at 90.2 degrees centigrade. One recrystallization from ether-acetone (500:1) gives 3-(l-benzimidazolyl)-a-hydroxypropionaldehyde diethylacetal of the formula cnzomomomooznm and melting at 91.5-93 degrees centigrade; weight 34.5 grams.

Analysis.Calcd. for C H N O c, 63.61; H, 7.63; N, 10.60. Found: C, 63,72; H, 7.42; N, 10.57.

Example 5 omcHmH) CHO-HCI is removed by filtration and washed with a small amount (ten milliliters) of ethanol; weight 7.49 grams (51 percent); melting point 152 degrees centigrade with decomposition after starting to discolor at 142 degrees centgrade.

8 I Analysis.Calcd. for C H ClN O Cl, 15.64; N, 12.36. Found: Cl, 15.09; N, 12.08.

Treatment of the hydrochloride obtained above with base according to the procedure of Example 3 provides the free base, }8-(l-benzimidazolyl)-a-hydroxypropionaldehyde.

Example 6 In a one-liter, round-bottomed flask is prepared a solution of 219 grams (1.5 moles) a, 8-epoxypropionaldehyde diethylacetal, 107 grams (1.5 moles) pyrrolidine and three milliliters methanol. A short time after the preparation of the solution a vigorous reaction takes place requiring cooling in an ice-bath to keep the reaction under control. After the reaction has subsided the mixture is warmed on a steam-bath for 45 minutes. The amber residual oil is distilled under reduced pressure through a ten-inch, glasshelices-packed column. The ,8 pyrrolidino on hydroxypropionaldehyde diethylacetal product, boiling point 88-90 degrees centigrade at 0.5 millimeters pressure, is collected as a colorless oil; yield of 233 grams (-71 percent); n 1.4522.

Analysis.-Calcd. for C H NO C, 60.80;. H, 10.67; N, 6.45. Found: C, 61.17; H, 10.58; N, 6.38.

In the same manner B-pyrrolidino-ot-hydroxypropionaldehyde dimethyl acetal, ethylene acetal, 1,2-propylene acetal and dibutyl acetal are prepared from the corresponding a,fi-epoxypropionaldehyde acetal.

Example 7 In a one-liter, three-necked, round-bottomed flask fitted with mechanical stirrer and reflux condenser is prepared a solution of 130.2 grams (0.60 mole) ,d-pyrroiidino-a-hydroxypropionaldehyde diethylacetal and 600 milliliters ten percent hydrochloric acid. The solution is heated on a steam-bath with continuous stirring for one and one-half hours, then concentrated on the steam-bath under reduced pressure, and the residual gum is dried with toluene. The reddish oily gum is dissolved in ,350 milliliters hot ethyl alcohol and then diluted with 350 milliliters ethyl acetate and milliliters ether. The pale cream-colored crystalline material, melting point 136-137 degrees centigrade, is collected in a yield of seventy grams (65 percent). The fi-pyrrolidino-a-hydroxypropionaldehyde hydrochloride Reaction of this base (freshly prepared) with phenylacetic acid provides ,B-pyrrolidino-u-hydroxypropionaldehyde phenylacetate [cH wHmNomomomCHO-QH CH COEH] In the same manner other acid addition compounds are prepared including the .citrate, succinate, propionate, furoate, B-cyclopentylpropionate, etc.

, Example 8 Following the procedureof Examples 1-7 there are prepared ,3 -(l-indolyl)=bz-hydroxyvaleraldehyde, the diethyl acetal and hydrochloride thereof; fi-morpholinou-hydroxy-a-methylisovaleraldehyde, the ethylene acetal and acetate thereof; fi-pyrrolidino-u-hydroXy-isobutyraldehyde, the dibutylacetal and hydrochloride thereof; B-pyrrolino-a-hydroxyisovaleraldehyde, the diethyl acetal and sulfate thereof; fl-(1,2,3,4 tetrahydroquinolino) a hydroxypropionaldehyde, the diethyl acetal and phosphate thereof; 5 (2-methylpyrrolidino)-a-hydroxypropionaldehyde, the 1,2-propylene acetal and sulfate thereof; fi-thiamorpholino-a-hydroxypropionaldehyde, the diethyl acetal and hydrochloride thereof; [i-hexarnethyleneimino-a-hydroxybutyraldehyde, the dimethyl acetal and hydrobromide thereof; and other B-(cyclic amino)-a-hydroxyalkanals, acetals and acid addition compounds thereof of the present invention.

It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

. 8 We claim: W n V 1. Acid addition salts of ,B=(carbomonocyclic amino)- a=hydroxypropionaldeliyde co'rhp'ounds of the formula '0 OH I1 I A HCGH-CH -N -12:

wherein m is a member of the group consisting of pyrrolidino,

20 ride.

6. B-( l-benzimidazolyl)-a-hydroxypropiona1dehyde hydrochloride.

No references cited. 

1. ACID ADDITION SALTS OF B-(CARBOMONOCYCLIC AMINO) A-HYDROXYPROPIONALDEHYDE COMPOUNDS OF THE FORMULA
 5. B-PIPERIDINO-A - HYDROXYPROPIONALDEHYDE HYDROCHALORIDE. 